Abstract
Abstract
Abstract 2910
Introduction:
MDS is characterized by defects in hematopoietic cell growth, differentiation and apoptosis. Ezatiostat, a glutathione S-transferase inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in leukemic blasts. The purpose of this Phase 2 study was to determine the efficacy and safety of ezatiostat on extended dose schedules in MDS.
Methods:
Patients (pts) with International Prognostic Scoring System Low or Int-1 risk MDS were enrolled. After initial dose-ranging in 14 pts, subsequent pts were randomized to 2 selected dose schedules: 37 pts at 3 gm daily for 2 weeks followed by a 1-week rest period and 36 pts at 2 gm daily for 3 weeks followed by a 1-week rest period. Treatment was given until lack of MDS response or unacceptable toxicity. A logistic regression analysis was conducted to identify significant MDS disease factors associated with hematologic improvement-erythroid (HI-E) rates as determined by the MDS International Working Group (2006) criteria.
Results:
Seventy-three pts were median age 73 years (range 48–89) 70% male, and with World Health Organization classification as follows: 11 refractory anemia (RA), 15 RA with ring sideroblasts, 5 RA with excess blasts-1, 24 refractory cytopenia with multilineage dysplasia, 9 MDS-unclassified, 3 MDS/Myeloproliferative disorder-U, 4 MDS-del 5q, and 2 Unknown. Fifty pts (68%) were INT-1 risk, 23 (32%) were Low risk; 27 pts (37%) had abnormal karyotypes with 23 (85%) complex/poor prognostic types. RBC transfusion-dependent pts required a median of 6 (range 4–19) U/8 weeks prior to study entry. Prior treatments included: 34 (47%) DNA methyltransferase (DMTI), 28 (38%) lenalidomide, 56 (77%) erythropoietin, and 32 (44%) growth factors. The HI-E response rate was similar for evaluable pts on the 2 schedules, therefore the data were pooled. The overall HI-E rate was 22% (13/60) [95% CI, 12.1%–34.2%]. The median duration of response was 34 weeks. Eleven of 38 (29%) RBC transfusion-dependent pts had transfusion reductions (reduction of 4U/8weeks) with 4 pts (11%) achieving transfusion independence. A 40% HI-E rate (6/15 pts) [95% CI, 16.3%–67.7%], was observed in pts who had prior lenalidomide, but no prior DMTI, with 5/11 pts (45%) achieving significant RBC transfusion reduction and 3/11 pts (27%) achieving transfusion independence. A 28% HI-E rate (5/18 pts) [95% CI, 9.7%–53.5%] was observed in pts who were lenalidomide and DMTI naive, with 4/8 pts (50%) achieving clinically significant RBC transfusion reduction. Sixteen pts had received prior DMTI but no prior lenalidomide treatment, a 0% HI-E rate (95%CI: 0%-20.6%) was reported. Prior DMTI treatment predicts a 6-fold decrease in the odds for HI-E response to ezatiostat (p=0.027). A 19% HI-Neutrophil (HI-N) rate was observed in 4/21 pts with neutropenia (95% CI, 5.4%–41.9%) and a bilineage (HI-E and HI-N) rate of 20% (95% CI, 5.7%–43.7%) in 4/20 pts with anemia and neutropenia. A 3.7% (95% CI, 0.1%–19%) HI-P rate was observed in 1/27 thrombocytopenic pts and a trilineage (HI-E, HI-N, HI-P) rate of 9.1% (95% CI, 0.2%–41.3%) in 1/11 pts with trilineage cytopenia. There were 2 cytogenetic complete responses, 1 with 45X,-Y[4], 46, XY [16] and 1 with del5q. A total of 431 ezatiostat cycles were given, median 4.0 (range 1–14). Only 15 cycles (3.5%) required dose reduction and 37 cycles (8.6%) dose delays. Most common ezatiostat-related adverse events (AEs) were non-hematologic Grade 1 and 2 gastrointestinal (GI) including: nausea (45%, 17%), diarrhea (25%, 8%), and vomiting (30%, 12%). Grade 3 events were: nausea (1%), diarrhea (3%), and vomiting (2%). Prior DMTI treatment was associated with an increased incidence of GI AEs. Pts with prior DMTI use had GI AEs (Grades 1, 2, 3): nausea (51%, 20%, 2%), vomiting (34%, 7%, 2%), diarrhea (22%, 10%, 5%). DMTI-naive pts had fewer GI AEs (Grades 1, 2, 3): nausea (39%, 15%, 0%), vomiting (26%, 15%, 2%), diarrhea (28%, 7%, 2%).
Conclusions:
Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant reduction in RBC transfusions, including transfusion independence, as well as HI-N and HI-P. Ezatiostat has shown clinically significant efficacy in lenalidomide naive and lenaliomide treated pts. The tolerability and activity profile of ezatiostat may offer an important treatment option for pts with low to INT-1 risk MDS.
Disclosures:
Raza: Telik, Inc.: Research Funding. Galili:Telik, Inc.: Research Funding. Godwin:Scripps Health: Honoraria. Boccia:Telik, Inc.: Research Funding. Rarick:Telik, Inc.: Research Funding. Meng:Telik, Inc.: Employment, Equity Ownership. Jones:Telik, Inc.: Employment, Equity Ownership. Brown:Telik, Inc.: Employment, Equity Ownership, Patents & Royalties. Young:Telik, Inc.: Employment, Equity Ownership. Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.